SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
Abstract Background The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. Methods RNA transcriptomes were obtained from tumor samples and online databases. Expression of different protein...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02429-8 |
| _version_ | 1818510729808969728 |
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| author | Chia-Hung Chien Wen-Bin Yang Jian-Ying Chuang Jung-Shun Lee Wei-An Liao Chih-Yuan Huang Pin-Yuan Chen An-Chih Wu Shun-Tai Yang Chien-Cheng Lai Pei-I Chi Jui-Mei Chu Siao Muk Cheng Chan-Chuan Liu Daw-Yang Hwang Shang-Hung Chen Kwang-Yu Chang |
| author_facet | Chia-Hung Chien Wen-Bin Yang Jian-Ying Chuang Jung-Shun Lee Wei-An Liao Chih-Yuan Huang Pin-Yuan Chen An-Chih Wu Shun-Tai Yang Chien-Cheng Lai Pei-I Chi Jui-Mei Chu Siao Muk Cheng Chan-Chuan Liu Daw-Yang Hwang Shang-Hung Chen Kwang-Yu Chang |
| author_sort | Chia-Hung Chien |
| collection | DOAJ |
| description | Abstract Background The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. Methods RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. Results High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. Conclusions SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future. |
| first_indexed | 2024-12-10T23:24:03Z |
| format | Article |
| id | doaj.art-74d3093ae005449f902018ee36784041 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T23:24:03Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-74d3093ae005449f902018ee367840412022-12-22T01:29:38ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-07-0141111410.1186/s13046-022-02429-8SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastomaChia-Hung Chien0Wen-Bin Yang1Jian-Ying Chuang2Jung-Shun Lee3Wei-An Liao4Chih-Yuan Huang5Pin-Yuan Chen6An-Chih Wu7Shun-Tai Yang8Chien-Cheng Lai9Pei-I Chi10Jui-Mei Chu11Siao Muk Cheng12Chan-Chuan Liu13Daw-Yang Hwang14Shang-Hung Chen15Kwang-Yu Chang16National Institute of Cancer Research, National Health Research InstitutesTMU Research Center of Neuroscience, Taipei Medical UniversityThe Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical UniversityDivision of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDivision of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityDepartment of Neurosurgery, Chang Gung Memorial Hospital at KeelungGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityDivision of Neurosurgery, Shuang-Ho Hospital, Taipei Medical UniversityNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesNational Institute of Cancer Research, National Health Research InstitutesAbstract Background The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. Methods RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. Results High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. Conclusions SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future.https://doi.org/10.1186/s13046-022-02429-8SH3GLB1TemozolomideResistanceMitochondrial functionsAutophagy |
| spellingShingle | Chia-Hung Chien Wen-Bin Yang Jian-Ying Chuang Jung-Shun Lee Wei-An Liao Chih-Yuan Huang Pin-Yuan Chen An-Chih Wu Shun-Tai Yang Chien-Cheng Lai Pei-I Chi Jui-Mei Chu Siao Muk Cheng Chan-Chuan Liu Daw-Yang Hwang Shang-Hung Chen Kwang-Yu Chang SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma Journal of Experimental & Clinical Cancer Research SH3GLB1 Temozolomide Resistance Mitochondrial functions Autophagy |
| title | SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| title_full | SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| title_fullStr | SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| title_full_unstemmed | SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| title_short | SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| title_sort | sh3glb1 related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma |
| topic | SH3GLB1 Temozolomide Resistance Mitochondrial functions Autophagy |
| url | https://doi.org/10.1186/s13046-022-02429-8 |
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